title: Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus.
abstract: OBJECTIVE
  Gene identification in small families segregating autosomal dominant sensorineural hearing loss presents a significant challenge. To address this challenge, we have developed a machine learning-based software tool, AudioGene v2.0, to prioritize candidate genes for mutation screening based on audioprofiling.
  
  
  METHODS
  We analyzed audiometric data from a cohort of American families with high-frequency autosomal dominant sensorineural hearing loss. Those families predicted to have a DFNA2 audioprofile by AudioGene v2.0 were screened for mutations in the KCNQ4 gene.
  
  
  RESULTS
  Two novel missense mutations and a stop mutation were detected in three American families predicted to have DFNA2-related deafness for a positive predictive value of 6.3%. The false negative rate was 0%. The missense mutations were located in the channel pore region and the stop mutation was in transmembrane domain S5. The latter is the first DFNA2-causing stop mutation reported in KCNQ4.
  
  
  CONCLUSIONS
  Our data suggest that the N-terminal end of the P-loop is crucial in maintaining the integrity of the KCNQ4 channel pore and AudioGene audioprofile analysis can effectively prioritize genes for mutation screening in small families segregating high-frequency autosomal dominant sensorineural hearing loss. AudioGene software will be made freely available to clinicians and researchers once it has been fully validated.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA. michael-hildebrand@uiowa.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.forename: Dylan
authors.initials: D
authors.lastname: Tack
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: McMordie
authors.forename: Adam
authors.initials: A
authors.lastname: DeLuca
authors.forename: In Ae
authors.initials: IA
authors.lastname: Hur
authors.forename: Carla
authors.initials: C
authors.lastname: Nishimura
authors.forename: Patrick
authors.initials: P
authors.lastname: Huygen
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Casavant
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005190:Family; D005799:Genes, Dominant; D034381:Hearing Loss / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006320:Hearing Tests; D006801:Humans; D051656:KCNQ Potassium Channels / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D012984:Software
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human